OU Neurology

NEUROPHARMACOLOGYCLINICAL PEARLS: MIGRAINE

Stephen M. Clayton, Jr., M.D.Assistant Professor

Department of NeurologyThe University of Oklahoma Health Sciences Center

OAPA 46th Annual CME Conference for Physician AssistantsSeptember 18-20, 2019

OU Neurology

RELEVANT DISCLOSURE & RESOLUTION

Under Accreditation Council for Continuing Medical Education guidelines disclosure must be made regarding relevant financial

relationships with commercial interests within the last 12 months.

Stephen M. Clayton, Jr., MDI have no relevant financial relationships or affiliations

with commercial interests to disclose

OU Neurology

EXPERIMENTAL OR OFF-LABEL DRUG/THERAPY/DEVICE DISCLOSURE

I will be discussing experimental or off-label drugs, therapies and/or devices that have not been approved by the FDA.

OU Neurology

NEUROPHARMACOLOGY CLINICAL PEARLS: MIGRAINE

Learning ObjectivesUpon completion of this session, participants will improve their competence and performance by being able to: Understand basic pathophysiology of migraine and explain these

principles in lay terms List various neurotransmitters (including small molecules and

neuropeptides) and receptors involved in migraine pathophysiology

Describe the major biochemical effect of drugs or drug classes commonly used to treat migraine and primary headache disorders

Recognize chemical structural similarities of certain medications used to treat migraine, either between each other or with neurotransmitters

OU Neurology

BASIC MIGRAINE PATHOPHYSIOLOGY

OU Neurology

MIGRAINE PATHOPHYSIOLOGYWhat Is Migraine? Genetic condition causing increased susceptibility to

“attacks” of neuronal dysfunction leading to stereotyped spells often with a variety of systemic manifestations

Attacks most often include: Headache Sensory phobias (light, sound, motion, temperature, smells) Nausea +/- vomiting ...but sometimes with “aura” = focal neurologic deficits

Classically 4 phases: prodrome, aura, pain, postdromeMany cannot appreciate all 4 phases, but remember painMany have multiple spell types A single spell type may evolve throughout life

OU Neurology

MIGRAINE PATHOPHYSIOLOGYWhat Causes Migraine Attacks?Unclear initial biochemical event but several

factors contributing to attacks:Wave of biochemical change at neuronal level =

“cortical spreading depression”Changes within trigeminovascular systemIncreased sensitization of cortical neurons via

thalamocortical projectionsUnderlying geneticsEnvironmental triggers (more on this later…)

OU Neurology

MIGRAINE PATHOPHYSIOLOGYCortical Spreading Depression (CSD)

Intense depolarization/excitation spreading a few millimeters per minute, followed by prolonged disruption in appropriate

signal conduction → “depression”

Unclear why but likely ↓ membrane resistance due to opening of nonselective cation channels → ions move along concentration gradients ↑ intracellular [Ca2+] and ↑ extracellular [K+] Depolarization → ↑ extracellular glutamate (excitatory) → ↑ NMDA

receptor activation (excitatory)

Large metabolic demand on cell to attempt restoring homeostasis by repleting intracellular energy stores ↓ ATP, O2, glucose, pH

OU Neurology

from Ayata C and Lauritzen M, 2015

20-HETE = 20-Hydroxyeicosatetraenoic acid (a metabolite of arachidonic acid); CGRP = calcitonin gene-related peptide;EDHF = endothelium-derived hyperpolarizing factor; EETs = epoxyeicosatrienoic acids (metabolites of arachidonic acid);

NE = norepinephrine; NK-A = neurokinin A; NO = nitric oxide; NPY = neuropeptide Y; PACAP = pituitary adenylatecyclase activating peptide; SP = substance P; VIP = vasoactive intestinal peptide

OU Neurology

MIGRAINE PATHOPHYSIOLOGYThalamocortical Projections

from Goadsby PJ, et al.

Au = auditory cortexEct = ectorhinal cortex

Ins = insular cortexLC = locus coeruleus

M1/M2 = primary and secondary motor cortex

PAG = periaqueductal grayPtA = parietal association cortex

RS = retrosplenial cortexRVM = rostral ventromedial medulla

S1/S2 = primary and secondary somatosensory cortex

SPG = sphenopalatine ganglionSuS = superior salivary nucleus

TCC = trigeminocervical complexTG = trigeminal ganglion

V1/V2 = primary and secondary visual cortex

OU Neurology

MIGRAINE PATHOPHYSIOLOGYGenetic Basis for Migraine Many genes implicated though none individually

convincing for all “run-of-the-mill” migraine Likely due to heterogeneity rather than lack of correlationMay explain why subsets of patients seem to respond better to

certain drug classes than others

For example, familial hemiplegic migraine: SCN1A (Nav1.1)

Severe myoclonic epilepsy of infancy (SMEI = Dravet syndrome) Generalized epilepsy with febrile seizures plus (GEFS+)

CACNA1A (P/Q type Cav2.1) ATP1A2 (Na+/K+-ATPase)

OU Neurology

MIGRAINE PATHOPHYSIOLOGYGenetic Basis for Migraine

from Sutherland and Griffiths

OU Neurology

MIGRAINE PATHOPHYSIOLOGYCommon TriggersConceptualize: Any sudden change can cause a CSD “chemical wave” Hormonal changes

Menarche Menses Pregnancy Menopause

Stress or stress let-down Insomnia Barometric pressure changes

Weather fronts Altitudinal changes

Smells Perfumes, colognes Candles, fumes, smoke

Bright lights

Stimulants Caffeine Energy drinks Nasal decongestants (i.e.,

pseudoephedrine, phenylephrine) Other sympathomimetics

Foods Monosodium glutamate (MSG) Nitrates & nitrites (e.g., deli meats) Tyramine (e.g., aged cheeses) Artificial sweeteners Alcohol Others

Skipping meals Dehydration

OU Neurology

MIGRAINE PATHOPHYSIOLOGYHow To Describe Migraine To Patients Migraine does not mean “bad headache”! People can

even have migraine attacks with no headaches! Migraine tends to run in families and is something you

were likely born with. Having migraine means your body is more sensitive to

the chemical changes that happen in your brain. Many things can trigger “attacks.” For people with

migraine, fewer triggers are required to start attacks. Because your brain is a tangle of wires controlling the

rest of your body, when the wires are overly sensitive during an attack many types of symptoms can occur…

OU Neurology

NEUROTRANSMITTERS IN MIGRAINE

OU Neurology

NEUROTRANSMITTERS IN MIGRAINEOverview Serotonin (5-HT) CGRP (calcitonin gene-

related peptide) Norepinephrine (NE) Histamine

Others Substance PNitric oxide (NO)Arachidonic acid

metabolitesPituitary adenylate

cyclase-activating polypeptide (PACAP)

Vasoactive intestinal peptide (VIP)

…and many more

OU Neurology

NEUROTRANSMITTERS IN MIGRAINESerotonin: Overview Serotonin = 5-hydroxytryptamine (5-HT) Interictal serotonin levels are lower in migraineurs,

likely leading to increased sensitization of receptorsMigraine attacks ↑ serotonin acutely↑ CGRP, glutamate, NO release↑ anxiety↑ nausea (via 5-HT3)↑ GI motility (via 5-HT4)

Serotonin

OU Neurology

NEUROTRANSMITTERS IN MIGRAINESerotonergic Projections

from Deen, et al.

OU Neurology

NEUROTRANSMITTERS IN MIGRAINESerotonin Receptors

adapted from Deen, et al.

In short,Prophylactic agents: 5-HT2 antagonists

Abortive agents: 5-HT1B/1D agonists

OU Neurology

NEUROTRANSMITTERS IN MIGRAINECGRP Calcitonin gene-related peptide: 37-residue protein Prominent pronociceptive effects Found in C and Aδ sensory fibersUpregulated in inflammatory and neurogenic pain

CGRP also acts as a potent arterial vasodilatorα- and β-CGRP receptors expressed in many body systemsMay serve protective role in cardiac disease

OU Neurology

NEUROTRANSMITTERS IN MIGRAINENorepinephrine (NE) NE produced in locus coeruleus in pons and

influences thalamocortical projectionsAnalogous to serotonergic projections from raphe nucleiNE prolongs activation of thalamic neurons ∴ may

perpetuate an abnormal excitability level for trigeminovascular system during attacks

Acts on α1, α2, β1, β2, β3 → mostly α1, α2, β1Net vasoconstriction↑ wakefulness and attention

OU Neurology

NEUROTRANSMITTERS IN MIGRAINEHistamine Produced in tuberomammillary nucleus in posterior

hypothalamus → project to entire CNS Histamine receptors H1, H2, H3 expressed in CNSChiefly excitatory for neurons, mostly via H1

Histamine also contributes to vasodilation

Histamine

Migraineurs have ↑ histamine levels ictally and interictally Sleep deprivation further ↑ CSF

histamine

OU Neurology

MIGRAINE MEDICATIONS

OU Neurology

Beta blockers Ca2+ channel blockers ACE inhibitors ARBs SNRIs TCAs Topiramate Valproic acid

CGRP inhibitors Botulinum toxin Melatonin Triptans NSAIDs Antiemetics Antihistamines Others

MIGRAINE MEDICATIONSOverview

ACE = angiotensin-converting enzymeARBs = angiotensin-receptor blockers

SNRIs = serotonin-norepinephrine reuptake inhibitorsTCAs = tricyclic antidepressants

CGRP = calcitonin-gene related peptideNSAIDs = non-steroidal anti-inflammatory drugs

Anti-

hype

rten

sive

sAn

ti-de

pres

sant

sAn

ti-se

izur

e

Mis

cella

neou

s Pr

ophy

laxi

sAb

ortiv

e Ag

ents

OU Neurology

MIGRAINE MEDICATIONSOverview Several drugs observed anecdotally to ↓ headache

frequency and later shown in rat models to decrease cortical spreading depression (Ayata, et al., 2006)

Amitriptyline TopiramatePropranolol Valproate

In general, pooled data in human trials also shows dose-dependent effects with positive results more robust beyond 8 weeks

Be sure to counsel patients that it will likely take several months to know if things are improving!

OU Neurology

MIGRAINE PROPHYLAXISBeta Blockers

Propranolol* Timolol*

*FDA-approved for migraine prophylaxis

Atenolol Metoprolol

Norepinephrine

Poorly understood; likely ↑ interictal serotonin levels through weak 5-HT1A/1B antagonism

OU Neurology

MIGRAINE PROPHYLAXISOther Antihypertensives (CCBs, ACEis, ARBs) Ca2+ channel blockers useful during strong depolarization

In subarachnoid hemorrhage-related vasospasm, nimodipine helps stabilize cerebral vasculature but otherwise not much effect

Analogous to cortical spreading excitation with migraine attacks Unclear mechanism though ↓ glutamate release possible Positive effects from early studies not well reproduced

ACE inhibitors have unclear mechanism though ↑ NO ARBs likely have pain modulation effect

Angiotensin II inhibits presynaptic GABA release Candesartan is only ARB sufficiently studied

Note: olmesartan and telmisartan have longer half-life and better oral bioavailability than candesartan and losartan

OU Neurology

MIGRAINE PROPHYLAXISSNRIs and TCAs Antinociceptive action of these antidepressants

poorly understood though possibly related to blockade of norepinephrine reuptake

Venlafaxine (SNRI) with weak evidenceNote: tramadol structurally similar to venlafaxine

TCAs are antagonists at 5-HT2A, 5-HT2C, H1, and α1Amitriptyline, doxepin, and nortriptyline have higher

affinity for these receptors, especially at 5-HT2A & 5-HT2C

Amitriptyline and nortriptyline also block SERT and NET, thereby functioning as SNRIs

OU Neurology

MIGRAINE PROPHYLAXISSNRIs and TCAs

Amitriptyline Nortriptyline Doxepin

Duloxetine Venlafaxine Tramadol

OU Neurology

MIGRAINE PROPHYLAXISAntiseizure Medications Topiramate has multiple effects: Enhanced GABAA-mediated inhibition AMPA/kainate antagonism = ↓ glutamate State-dependent Na+ channel blockade High-voltage-activated Ca2+ channel inhibitionWeak carbonic anhydrase activity

Topiramate

Valproic acid blocks GABA transaminase → ↑ GABA (inhibitory)

γ-aminobutyric acid (GABA)Valproic acid

OU Neurology

MIGRAINE PROPHYLAXISCGRP Inhibitors Initial small-molecule CGRP antagonists were limited

by poor oral bioavailability and/or hepatotoxicity In trials: ubrogepant (abortive), atogepant (prophylactic)

CGRP receptor (gray) with first “-gepant” in

development, olcegepant, bound

(yellow ball-and-stick)

OU Neurology

MIGRAINE PROPHYLAXISCGRP Inhibitors Several subcutaneous injectable monoclonal

antibodies were approved by the FDA in 2018: Erenumab-aooe (Aimovig) – binds CGRP receptorGalcanezumab-gnlm (Emgality) – binds CGRP ligand Fremanezumab-vfrm (Ajovy) – binds CGRP ligand

Because CGRP receptors expressed throughout body, long-term side effects are thus far undetermined Constipation is most reported side effect Unclear if gastrointestinal mucosal integrity and other

wound healing compromised Also unclear if increased cardiovascular risks possible

OU Neurology

MIGRAINE PROPHYLAXISBotulinum Toxin In animal models, injected botulinum toxin taken up

by local sensory nerve endings, transported along axons to the trigeminal ganglion, and transcytosed to dural sensory afferentsCleaved SNAP-25 likely ↓ Ca2+-dependent CGRP release

↑ baseline interictal CGRP levels predicts better response to onabotulinum toxinCan we screen patients in future?Will CGRP antagonists replace Botox for chronic migraine?

OU Neurology

MIGRAINE PROPHYLAXISMelatonin Light signals to suprachiasmatic nucleus of hypothalamus

control melatonin production in pineal gland → regulates circadian rhythm

MT1 and MT2 receptor activation Valproic acid ↑ mRNA expression of MT1 receptor

↓ CGRP release Analgesic effect GABAergic potentiation↓ prostaglandin synthesis↑ endorphin release → opioid μ agonism

Indole + serine = tryptophan →→ serotonin →→ melatonin

Melatonin

OU Neurology

MIGRAINE ABORTIVESTriptans 5-HT1B/1D agonists ∴ ↑ serotonergic inhibition↓ vasodilation↓ release of vasoactive neuropeptides, esp. CGRP↓ nociceptive neurotransmission

Indole group found in serotonin common to triptans Useful for both acute migraine and cluster attacks Contraindicated if coronary artery diseaseAlso avoid in hemiplegic migraine or brainstem aura

Limit use to 2 days per week! One of the worst to cause medication overuse headaches!

OU Neurology

MIGRAINE ABORTIVESTriptans

SerotoninFrovatriptan (Frova)

Sumatriptan (Imitrex) Rizatriptan (Maxalt)

Naratriptan (Amerge)Almotriptan (Axert)

Eletriptan (Relpax) Zolmitriptan (Zomig)

OU Neurology

MIGRAINE ABORTIVESNSAIDs Prostaglandin E2 (PGE2) and other prostaglandins

produce hyperalgesia NSAIDs inhibit cyclooxygenase 2 (COX-2),

decreasing production of PGE2 in the setting of inflammationMay also have effects on serotonin and NO

Indomethacin useful for trigeminal autonomic cephalalgias, particularly hemicraniasContains indole group like serotonin and triptans as well

OU Neurology

MIGRAINE ABORTIVESNSAIDs

Indomethacin Melatonin

Aspirin Naproxen Ibuprofen

Serotonin

OU Neurology

MIGRAINE ABORTIVESAntiemetics Emesis mediated through D2, 5-HT3, NK1, H1, M1Best evidence in migraine for prochlorperazineMetoclopramide also 5-HT4 agonism → pro-motility

Selective 5-HT3 antagonists, e.g., ondansetron, actually worsen headache in ~15% of migraineursthough unclear whyNote: mirtazapine is a strong inhibitor at H1, α2, 5-HT2, &

5-HT3 (+ “indirect agonist” activity at 5-HT1A via α2 effect) May be a reasonable option for migraine with prominent nausea

and concomitant depression but not studied UpToDate lists headache prophylaxis as off-label use

OU Neurology

MIGRAINE ABORTIVESAntiemetics

Promethazine

Metoclopramide

ChlorpromazineProchlorperazine

Ondansetron

Dopamine

Mirtazapine

OU Neurology

MIGRAINE ABORTIVESAntihistamines In addition to H1 antagonism, cyproheptadine,

diphenhydramine, hydroxyzine all have 5-HT2receptor antagonismCyproheptadine also has D3 antagonism and is

antimuscarinic, likely due to structural similarity to TCAs

Cyproheptadine Diphenhydramine Hydroxyzine

OU Neurology

OTHER MIGRAINE MEDICATIONSMagnesiumMg2+ is essential cofactor for 350+ enzymesMg2+ blocks glutamate/glycine-coactivating NMDA

receptors, preventing influx of Ca2+ → ↓ excitation Memantine also blocks NMDA receptors

Mg2+ likely has several other mechanisms: Decreasing release of substance P Enhance Na+/K+-ATPase activity, allowing clearance of glutamate Modulate mitochondrial ability to handle oxidative stress

↓ Mg2+ associated with triggering CSD↓ Mg2+ → ↑ intracellular Ca2+ → ↑ glutamate and

aspartate release → ↑ serotonin IV bolus (!) as abortive; PO daily for prophylaxis

OU Neurology

OTHER MIGRAINE MEDICATIONSRiboflavin (Vitamin B2) Precursor for coenzymes flavin mononucleotide

(FMN) and flavin adenine dinucleotide (FAD)Mitochondrial function, including electron transport chainVitamin metabolism (A, niacin, B6, folate, B12, D, K)

Rich source in milk, cheese, and eggs; need 1.5 mg/d For migraine, recommended off-label dose is 400 mg daily Zempleni et al. reported max. 27 mg absorbed per oral

dose ∴ do we really need 400 mg daily?

Unclear specific mechanism in migraineCoenzyme Q10 may also be useful for migraine

OU Neurology

OTHER MIGRAINE MEDICATIONSHerbal Extracts for Prophylaxis Butterbur (Petasites hybridus) Vasodilatory effect via L-type Ca2+ channel

antagonism Anti-inflammatory effect via leukotriene

inhibition Isopetasin modulates TRPA1 → ↓ nociception

Acetaminophen metabolites also modulate TRPA1

Feverfew (Tanacetum parthenium) Active constituent is parthenolide Anti-inflammatory effect via ↓ NF-κB activity →

modulates inducible NO synthase activity → ↓ NO Also modulates TRPA1

Parthenolide

Isopetasin

OU Neurology

TREATING MIGRAINE

OU Neurology

TREATING MIGRAINEMedications: Abortive AgentsMild/infrequent Acetaminophen or NSAID No response and no contraindication Triptan If using 3+ days per week, add prophylactic

Prominent nausea Add antiemetic Difficulty getting to sleep Add antihistamineHas anxiety? Choose hydroxyzine

Remember: Select therapies based on medical comorbidities and side effect profiles!

OU Neurology

TREATING MIGRAINEAddressing Medication OveruseNerves become hypersensitive with certain medications taken >

2 days/wk causing “rebound” headaches/attacks

First have to ask the question: “Are you taking any…” Caffeine

Coffee, tea, sodas; if so, how much? 2 pots? 1/2 gallon? 12-pack?

NSAIDs or acetaminophen (including combos like Excedrin Migraine, BC Powder, Goody’s Powder, Tylenol PM, Fioricet, Midrin, etc.)

Nasal decongestants (i.e., Sudafed, “-D” in Claritin-D, etc.) Muscle relaxants Opioids and opiates Triptans (including combos, i.e., Treximet)

“How often are you taking each of these?” Avoid use of these medications for at least 4-8 weeks

OU Neurology

TREATING MIGRAINEProphylactic Medications: Side Effects Beta blockers – hypotension, sedation, depression, asthma Ca2+ channel blockers, ACE inhibitors, ARBs – hypotension SNRIs – insomnia, depression (initiation) TCAs – weight gain, sedation, constipation, depression (initiation) Topiramate – weight loss, paresthesias, taste changes (esp.

carbonated beverages), word-finding issues, decreased sweating, kidney stones, glaucoma

Valproic acid – weight gain, hair loss, polycystic ovarian synd. CGRP inhibitors – constipation, injection site and/or allergic rxn. Botulinum toxin – weakness, injection site pain (31 sites) Melatonin – sedation, hallucinations Magnesium – loose stools

OU Neurology

TREATING MIGRAINEMedications: Prophylactic Agents Constipation Magnesium Insomnia Melatonin Hypertension Antihypertensive Depression TCA or SNRI Pt. Avoids Rx Nutraceuticals (e.g., riboflavin)

Remember: Select therapies based on medical comorbidities and side effect profiles…while minimizing total pills!

OU Neurology

TREATING MIGRAINESpecial Populations: PregnancyAbortives AcetaminophenProphylactics Based on Pregnancy ClassPregnancy Class B Cyproheptadine

Pregnancy Class C Amitriptyline, Doxepin Gabapentin Metoprolol,

Propranolol, Timolol Verapamil

Pregnancy Class D Atenolol Topiramate

Pregnancy Class X Divalproex

OU Neurology

TREATING MIGRAINESpecial Populations: Children Abortive Acetaminophen, Ibuprofen, Naproxen, or Triptan

Rizatriptan ODT or tablet = Maxalt (FDA-approved for 6+) Sumatriptan/naproxen tablet = Treximet (FDA-approved for 12+) Almotriptan tablet = Axert (FDA-approved for 12+) Zolmitriptan ODT, tablet, nasal = Zomig (FDA-approved for 12+)

Prophylactic As below Topiramate (FDA-approved for 12+) → Caution with athletes! Cyproheptadine → 1st-line for children 3-8 yrs. (Unapproved use) Gabapentin (all ages; not FDA-approved) Propranolol (ages 8+; not FDA-approved) Amitriptyline (ages 8+; not FDA-approved) Divalproex (ages 2+ [black box < 2 yrs.]; not FDA-approved) Riboflavin, Magnesium, Melatonin

OU Neurology

TREATING MIGRAINEMedications: Summary Abortives Useful option for all patients Best if taken at first sign of migraine, i.e., before the pain

starts!

Prophylactic agents indicated if:More than 1-2 headache days per week Attacks are so long or debilitating that affect work productivity Hemiplegic migraine Intractable drug-induced headaches

Select therapies based on medical comorbidities and side effect profiles. Remind patients that they may not notice a difference

within first 2 months!

OU Neurology

NEUROPHARMACOLOGY CLINICAL PEARLS: MIGRAINE

Learning ObjectivesUpon completion of this session, participants will improve their competence and performance by being able to: Understand basic pathophysiology of migraine and explain these

principles in lay terms List various neurotransmitters (including small molecules and

neuropeptides) and receptors involved in migraine pathophysiology

Describe the major biochemical effect of drugs or drug classes commonly used to treat migraine and primary headache disorders

Recognize chemical structural similarities of certain medications used to treat migraine, either between each other or with neurotransmitters

OU Neurology

NEUROPHARMACOLOGY CLINICAL PEARLS: MIGRAINE

Summary 5-HT1B and 5-HT1D are inhibitory autoreceptors so 5-HT1B/1D

agonists for acute attacks; triptans look like serotonin 5-HT2 receptor activation is excitatory; 5-HT2 antagonists help

for migraine prophylaxis CGRP is potent nociceptive neurotransmitter → CGRP inhibitors NE, histamine, NO, and many others implicated in migraine SNRIs & TCAs likely effective in migraine from NE & 5-HT effects Valproic acid and topiramate potentiate GABA Mechanisms for antihypertensives unclear Future: individualizing prophylactic and abortive therapies based

on each patient’s predisposing mechanism for migraine

OU Neurology

REFERENCES

“3N7S: Crystal structure of the ectodomain complex of the CGRP receptor, a Class-B GPCR, reveals the site of drug antagonism.” Research Collaboratory for Structural Bioinformatics Protein Data Bank. <http://www.rcsb.org/structure/3N7S>. Accessed 02/17/19.

“Angiotensin II receptor blocker.” Table 1: Comparison of ARB pharmacokinetics. Wikipedia. <https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocker>. Accessed 02/17/19.

Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of Cortical Spreading Depression in Migraine Prophylaxis. Ann Neurol. 2006;59:652-661.

Ayata C, Lauritzen M. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. Physiol Rev 95: 953–993, 2015. doi:10.1152/physrev.00027.2014.

Bajwa ZH, Smith JH. “Preventative treatment of migraine in adults.” UpToDate. <https://www.uptodate.com/contents/preventive-treatment-of-migraine-in-adults>. Accessed 02/11/19.

Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia. 2002 Jun;22(5):345-53.

Buchanan TM, Ramadan NM. Prophylactic pharmacotherapy for migraine headaches. Semin Neurol. 2006 Apr;26(2):188-98. Casucci G, Villani V, Frediani F. Central mechanism of action of antimigraine prophylactic drugs. Neurol Sci. 2008;29:S123-

S126. doi: 10.1007/s10072-008-0902-9. Cashman JM. The mechanisms of action of NSAIDs in analgesia. Drugs. 1996;52 Suppl 5:13-23. Cernuda-Morollón E, Ramón C, Martínez-Camblor P, Serrano-Pertierra E, Larrosa D, Pascual J. OnabotulinumtoxinA decreases

interictal CGRP plasma levels in patients with chronic migraine. Pain. 2015 May;156(5):820-4. doi: 10.1097/j.pain.0000000000000119.

Chrusciel, Deepti. “Subacute Management of Headaches in Children.” May 16, 2014. PowerPoint lecture. Chugani DC, Niimura K, Chaturvedi S. Increased brain serotonin synthesis in migraine. Neurology. 1999;53:1473–1479. Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on newer generation

compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65.

OU Neurology

REFERENCES (cont.)

Deen M, Christensen CE, Hougaard A, Hansen MD, Knudsen GM, Ashina A. Serotonergic mechanisms in the migraine brain – a systematic review. Cephalalgia. 2017;37(3):251-264. doi: 10.1177/0333102416640501.

Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltrn E, Vigneri S, Edvinsson L, Maassen Van Den Brink A; European Headache Federation School of Advanced Studies (EHF-SAS). Blocking CGRP in migraine patients - a review of pros and cons. Headache Pain. 2017 Sep 25;18(1):96. doi: 10.1186/s10194-017-0807-1.

DeMaagd G. The pharmacological management of migraine, part 1: overview and abortive therapy. Pharmacy and Therapeutics. 2008 Jul; 33(7): 404-416.

DeMaagd G. The pharmacological management of migraine, part 2: preventative therapy. Pharmacy and Therapeutics. 2008 Aug;33(8):480-7.

Gariballa S, Ullegaddi R. Riboflavin status in acute ischaemic stroke. Eur J Clin Nutr. 2007 Oct;61(10):1237-40. Gelfand, Amy A. Pediatric and Adolescent Headache. Continuum. 2018; 24(4, Headache):1108-1136. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of

Sensory Processing. Physiol Rev. 2017;97(2):553-622. Gordon DL. Headache and Migraine. Oct. 24, 2018 PowerPoint presentation to medical students at the University of

Oklahoma College of Medicine. Hebestreit JM, May A. Topiramate modulates trigeminal pain processing in thalamo-cortical networks in humans after single

dose administration. PLoS One. 2017 Oct 9;12(10):e0184406. doi: 10.1371/journal.pone.0184406. Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene–related peptide in peripheral and central pain mechanisms

including migraine. Pain. 2017 Apr; 158(4): 543–559. doi: 10.1097/j.pain.0000000000000831. Jackson JL, Cogbill E, Santana-Davila R, et al. A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of

Migraine Headache. PLoS One. 2015;10(7):e0130733. Published 2015 Jul 14. doi:10.1371/journal.pone.0130733. Lackovic Z, Filipovic B, Matak I, Helves Z. Activity of botulinum toxin type A in cranial dura: implications for treatment of

migraine and other headaches. Br J Pharmacol. 2016 Jan;173(2):279-91. doi: 10.1111/bph.13366.

OU Neurology

REFERENCES (cont.)

Lévy E, Margolese HC. Migraine headache prophylaxis and treatment with low-dose mirtazapine. Int Clin Psychopharmacol. 2003 Sep;18(5):301-3.

Lienhart W, Gudipati V, Macheroux P. The human flavoproteome. Arch Biochem Biophys. 2013 Jul 15; 535(2): 150–162. doi: 10.1016/j.abb.2013.02.015.

Long R, Zhu Y, Zhou S. Therapeutic role of melatonin in migraine prophylaxis: A systematic review. Medicine (Baltimore). 2019 Jan;98(3):e14099. doi: 10.1097/MD.0000000000014099.

Lucas S. The Pharmacology of Indomethacin. Headache. 2016 Feb;56(2):436-46. doi: 10.1111/head.12769. Mack, Kenneth J. “Preventative treatment of migraine in children.” UpToDate. Accessed 10/29/18. Maryanoff BE. Phenotypic Assessment and the Discovery of Topiramate. ACS Med Chem Lett. 2016;7(7):662-665.

doi: 10.1021/acsmedchemlett.6b00176. Meng J, Wang J, Lawrence G, Dolly JO. Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by

botulinum toxins reflects their anti-nociceptive potential. J Cell Sci. 2007 Aug 15;120(Pt 16):2864-74. Nestler EJ, Hyman SE, Holtzman DM, Malenka RC. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience,

Third Edition. 2015. McGraw-Hill. Noseda R, Borsook D, Burstein R. Neuropeptides and Neurotransmitters That Modulate Thalamo-Cortical Pathways Relevant

to Migraine Headache. Headache. 2017 May;57 Suppl 2:97-111. doi: 10.1111/head.13083. Pinto JT, Zempleni J. Riboflavin. Adv Nutr. 2016 Sep 15;7(5):973-5. doi: 10.3945/an.116.012716. Porter RJ, Dhir A, Robert L Macdonald RL, Rogawski MA. Mechanisms of Action of Antiseizure Drugs (Chapter 39). Handbook

of Clinical Neurology, Epilepsy, Part II 2012;108:663-681. Raij L. Workshop: hypertension and cardiovascular risk factors: role of the angiotensin II-nitric oxide interaction. Hypertension.

2001 Feb;37(2 Pt 2):767-73. Reuter U, Chiarugi A, Bolay H, Moskowitz MA. Nuclear factor-kappaB as a molecular target for migraine therapy. Ann Neurol.

2002 Apr;51(4):507-16.

OU Neurology

REFERENCES (cont.)

Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012 Apr 24;78(17):1337-45. doi: 10.1212/WNL.0b013e3182535d20.

Sutherland HG, Griffiths LR. Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders. Headache. 2017 Apr;57(4):537-569. doi: 10.1111/head.13053.

Thompson DF, Saluja HS. Prophylaxis of migraine headaches with riboflavin: A systematic review. J Clin Pharm Ther. 2017 Aug;42(4):394-403. doi: 10.1111/jcpt.12548.

“Tricyclic antidepressants.” Wikipedia. <https://en.wikipedia.org/wiki/Tricyclic_antidepressant>. Accessed 02/16/19. Data for affinities of tricyclic antidepressants derived from data from: Roth BL, Driscol J. PDSP Ki Database. Psychoactive Drug Screening Program (PDSP). Univ. of North Carolina at Chapel Hill and the US National Institute of Mental Health. <https://pdsp.unc.edu/databases/kidb.php>. Retrieved August 14, 2017.

Tsuda K. Renin-Angiotensin system and sympathetic neurotransmitter release in the central nervous system of hypertension. Int J Hypertens. 2012;2012:474870. doi: 10.1155/2012/474870.

Vogler B, Rapoport AM, Tepper SJ, Sheftell F, Bigal ME. Role of melatonin in the pathophysiology of migraine: implications for treatment. CNS Drugs. 2006;20(5):343-50.

Xing J, Li D, Li H. Role of GABA Receptors in Nitric Oxide Inhibition of Dorsolateral Periaqueductal Gray Neurons. Neuropharmacology. 2008 Mar; 54(4): 734–744. doi: 10.1016/j.neuropharm.2007.12.008.

Yuan H, Silberstein SD. Histamine and Migraine. Headache. 2018 Jan;58(1):184-193. doi: 10.1111/head.13164. Zempleni J, Galloway JR, McCormick DB. Pharmacokinetics of orally and intravenously administered riboflavin in healthy

humans. Am J Clin Nutr. 1996 Jan;63(1):54-66. Zou YX, Zhang XH, Su FY, Liu X. Importance of riboflavin kinase in the pathogenesis of stroke. CNS Neurosci Ther. 2012

Oct;18(10):834-40. doi: 10.1111/j.1755-5949.2012.00379.x.

OU Neurology

THE END